The overall goal of the proposed research is to develop a clinical assay that can be used as a biomarker of neuronal damage and death in patients with multiple sclerosis (MS). Such an assay would aid in predicting the clinical course and pathological subtypes and would enable better treatment of individual patients. The research is relevant to the Clinical Immunology Branch of the Division of Allergy, Immunology, and Transplantation of the National Institute of Allergy and Infectious Disease (NIAID) that supports studies of the immune system in health and the cause, pathogenesis, diagnosis, prevention, and treatment of disease caused by immune dysfunction. The Phase I research is based on recent discoveries by Dr. Claude Genain and colleagues at the University of California, San Francisco. The specific aims of the Phase I research are as follows: Aim 1: To perform an extensive evaluation of anti-neuronal antibodies in serum and cerebrospinal fluid of patients with a clinically isolated syndrome, relapsing remitting or progressive MS, and correlate these measurements with clinical and MRI outcomes Aim 2: To identify the cellular targets for the destructive antibodies on human neurons. MS is a chronic disorder of central nervous system white matter affecting 350,000 Americans and over one million individuals worldwide. MS affects women twice as often as men, and thus also represents a significant women's health issue. This project is expected to result in development of a simple, fast, and reliable biomarker that can be used by clinicians to identify patients at risk to develop neuronal and axonal injury, in MS as well as other neurological disorders. This would enable physicians to utilize more effectively neuroprotective strategies that are in development, or already in use for patient subgroups (such as matrix metalloprotease inhibitors, statins, inhibitors of glutamate excitotoxicity, complement inhibitors, neurotrophins, and progenitor or stem cell approaches). In addition, the research could result in identification of novel targets for therapies using inhibitors of autoantibodies. [unreadable] [unreadable]